Compositions containing alpha-2-adrenergic agonist components

ABSTRACT

Compositions useful for improving effectiveness of alpha-2-adrenergic agonist components include carrier components, alpha-2-adrenergic agonist components, solubility enhancing components which aid in solubilizing the alpha-2-adrenergic agonist components. In one embodiment, the alpha-2-adrenergic agonist components include alpha-2-adrenergic agonists. In another embodiment, the solubility enhancing components include carboxymethylcellulose.

This application is a continuation of U.S. patent application Ser. No.15/048,607, filed Feb. 19, 2016, which is a continuation of U.S. patentapplication Ser. No. 14/484,017, filed Sep. 11, 2014, now U.S. Pat. No.9,295,641, issued Mar. 29, 2016, which is a continuation of U.S. patentapplication Ser. No. 12/482,783, filed Jun. 11, 2009, now U.S. Pat. No.8,858,961, issued Oct. 14, 2014, which is a continuation-in-part of U.S.patent application Ser. No. 10/928,906 filed Aug. 27, 2004, nowabandoned, which is a continuation-in-part of U.S. patent applicationSer. No. 10/691,912, filed Oct. 22, 2003, now abandoned, which is acontinuation of U.S. patent application Ser. No. 10/236,566 filed Sep.6, 2002, now U.S. Pat. No. 6,641,834, issued Nov. 4, 2003, which is acontinuation of U.S. patent application Ser. No. 09/904,018, filed Jul.10, 2001, now U.S. Pat. No. 6,627,210, issued Sep. 30, 2003, whichclaims benefit of U.S. Provisional Patent Application No. 60/218,200filed Jul. 14, 2000, all of which are hereby incorporated herein byreference.

BACKGROUND OF THE INVENTION

The present invention relates to compositions containingalpha-2-adrenergic agonist components. More particularly, the inventionrelates to such compositions in which the alpha-2-adrenergic agonistcomponents have enhanced solubility at the therapeutically effectiveconcentrations, in which a solution comprising the alpha adrenergiccomponents have substantially similar efficacy at a given pH andconcentration as compared to a second solution comprising the alphaadrenergic component at a more acid pH and higher concentration.

Alpha-2-adrenergic agonist components include chemical entities, such ascompounds, ions, complexes and the like, which are effective to act onor bind to alpha-2-adrenergic receptors and provide a therapeuticeffect. As used herein, the term the term “alpha-2-adrenergic agonistcomponent” means the agonists themselves and any and all precursors,salts and esters thereof, metabolites thereof and combinations thereof.

One of the continuing challenges of formulating compositions havingalpha-2-adrenergic agonist components is to render such components moreeffective. For example, alpha-2-adrenergic agonist components in liquidcompositions often benefit from being soluble in the liquid carriers ofsuch compositions. Such solubility promotes uniform and accurateadministration.

Additionally, the dispensed or administered alpha-2-adrenergic agonistcomponents should advantageously be soluble in biological systems orenvironments, for example, for effective or enhanced in vivo diffusionthrough cell membranes or lipid bilayers. Some alpha-2-adrenergicagonist components, with higher pKa's, greater than about 7, including,for example, brimonidine, tend to diffuse very well through lipidmembranes at pH values near or above their pKa, because when in asolution in such circumstances they are predominantly uncharged inneutral to alkaline biological environments. Being more hydrophobic, atthis raised pH they are better able to penetrate cellular membranes.

However, at pH values above about 7 a countervailing factor comes intoplay. Some of these same alpha-2-adrenergic agonist components tend tobecome less soluble at neutral to alkaline biological pH values inaqueous solutions. Such a decrease in aqueous solubility means that lessof the active agent is available in solution to penetrate cellularmembranes in order to deliver its therapeutic effect. Thus, even thoughthe soluble compound is more able to penetrate cellular membranesbecause of its uncharged state, there is less of the component presentin solution to provide such a therapeutic effect. Thus, there is a riskthat precipitation of the alpha-2-adrenergic agonist component at pHvalues above about 7.0 will render the alpha-2-adrenergic agonistcomponents less effective and/or their therapeutic effects more variableat a given dosage.

Furthermore, solubilized alpha-2-adrenergic agonist components provideother benefits, for example, reduced irritation to tissues that interactwith alpha-2-adrenergic agonist components, than do insolublealpha-2-adrenergic agonist components.

A specific alpha-2-adrenergic agonist, brimonidine, has been sold as a0.2% aqueous ophthalmic solution under the trade name ALPHAGAN®. Thissolution comprises 0.2% brimonidine tartrate, and is formulated at pH6.5 in a citrate buffer with 0.05% benzalkonium chloride as apreservative.

Additionally, brimonidine is also marketed as a 0.15% ophthalmicsolution under the trade name ALPHAGAN P®. This solution is formulatedat pH 7.2 and contains carboxymethylcellulose and 0.005% of a stabilizedoxy-chloro preservative) (PURITE®).

Katz, et al., J. Glaucoma 11:119 (April 2002), entitled Twelve-MonthEvaluation of Brimonidine Purite Versus Brimonidine in Patients withGlaucoma or Ocular Hypertension discloses that a formulation containing0.15% brimonidine and a PURITE® preservative has a similar efficacy whenadministered topically in lowering intraocular pressure as a secondformulation containing 0.2% brimonidine. This paper is herebyincorporated by reference as part of this disclosure.

There continues to be a need for new compositions containingalpha-2-adrenergic agonist components which combine a high degree ofefficacy with a low incidence of side effects, including systemic sideeffects.

SUMMARY OF THE INVENTION

The present invention is based on the discovery of newalpha-2-adrenergic agonist component-containing compositions which areable to deliver the active agent more effectively to the target cell ortissue. This increase in efficacy can be attributed to two factors:solubility and a neutral or alkaline pH. It will be understood that pHvalues given in this specification are to be measured at roomtemperature.

In one embodiment, the present compositions contain certain materialswhich are effective in at least aiding or assisting in solubilizing thealpha-2-adrenergic agonist components in the compositions, andpreferably in environments to which the compositions are administered orintroduced, for example, biological environments, such as the human eye.Preferably, aqueous solubility of alpha-2-adrenergic agonist componentsin accordance with the present invention facilitates predicable andconsistent delivery of the therapeutic effect to the target cell ortissue.

In another embodiment, the present invention is drawn to aqueoussolutions containing alpha-2-adrenergic agonist components which have apH above about 7.0, preferably between about pH 7.0 and about pH 8.5,more preferably between about pH 7.2 and about pH 8.2 or about pH 7.2,even more preferably between about pH 7.5 and about pH 8.0 or at aboutpH 7.7. In this embodiment the aqueous solution may optionally contain amaterial or mixture of materials which is effective in at least aidingor assisting in solubilizing the alpha-2-adrenergic agonist components.Alternatively, the solution may lack such exogenous solubilizingmaterials and comprise or consist essentially of a solublealpha-2-adrenergic agonist component in aqueous solution at a pH valueas indicated above. In this aspect, the neutral or alkaline pH permitsthe passage of the alpha-2-agonist component through cellular membranesmore easily.

Thus, when the pH of the soluble alpha-2-adrenergic agonist component isabove about 7.0, it aids in the transport of such components acrosslipid membranes. Also, since the alpha adrenergic components aresoluble, the dosage of the alpha-2-adrenergic agonist is reliable andreproducible.

Certain alpha-2-adrenergic components have been known to haveundesirable side effects. For example, clonidine and tizanidine havebeen shown to have respiratory and cardiovascular depressive andsedative effects when administered systemically. Thus, anyalpha-2-adrenergic agonist formulation in which efficacy can bemaintained at a lower effective dose than is commonly used would beclearly advantageous.

In another aspect of the invention, alpha-2-adrenergic agonistcomponent-containing compositions have been discovered which includepreservatives that provide substantial advantages, for example, reducedadverse interactions with the alpha-2-adrenergic agonist componentsand/or with the patients to whom the compositions are administered,while maintaining preservative effectiveness. Preferably, the alphaadrenergic composition is brimonidine.

The present compositions preferably enhance or maintain theeffectiveness of previous alpha-2-adrenergic agonist components, whileproviding additional benefits not present in prior formulations. This isaccomplished by keeping the alpha-2-adrenergic agonist component inaqueous solution while simultaneously maintaining a pH value above about7.0, preferably between about pH 7.0 and about pH 8.5, more preferablybetween about pH 7.2 and about pH 8.2 or about pH 7.2, even morepreferably between about pH 7.5 and about pH 8.0 or at about pH 7.7. Byincreasing the membrane permeability of the alpha-2-adrenergic agonistcomponent it is possible to lower the concentration of the alpha 2agonist in the administered formulation, particularly (but notexclusively) brimonidine, thereby reducing any systemic side effects,particularly when the formulation is given systemically.

Within the ambit of some embodiments of the present invention theconcentration of brimonidine (including and its pharmaceuticallyacceptable salts such as the tartrate) in a topical ophthalmicformulation may be reduced below 0.2% (w/v) (preferably between about0.01% and about 0.1% (w/v)) while maintaining the same or substantiallysimilar efficacy as the product ALPHAGAN®; a 0.2% brimonidine tartrateformulation having a pH of about pH 6.6 to about pH 6.8. In anotherembodiment, the concentration of brimonidine is preferably about 0.01%to about 0.15% (w/v) at a pH above about 7.0 (preferably about pH 7.2-,about pH 7.7, with any difference in efficacy between the twoformulations lacking any substantial difference in efficacy.

As shown in FIG. 1, the solubility of a representativealpha-2-adrenergic agonist, 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline tartrate, decreases as the pH of the aqueous solutionincreases. The pKa of 5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline isabout 7.4. As the solution becomes more alkaline, the majority ofmolecules in solution become electronically neutral, and thereforeincreasingly hydrophobic.

FIG. 1 shows that various solutions containing5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline all share the samegeneral trend; their solubility decreases with increasing pH. The curveidentified with a cross (

) is an aqueous solution containing the active agent with no addedcarboxymethylcellulose (CMC); such solutions are within the scope ofcertain embodiments of this invention.

In one aspect, the effectiveness of the alpha-2-adrenergic agonistcomponents are increased by increasing the solubility of thealpha-2-adrenergic agonist components, preferably at pH values higherthan neutral. In this aspect of the invention, the invention includes,in addition to the alpha-2-adrenergic agonist components, solubilityenhancing components (SECs) in amounts effective to enhance thesolubility of the alpha-2-adrenergic agonist components at a given pH.Preferably, these SECs are anionic in nature, and even more preferably,they are polymeric in nature. In one embodiment the SEC is a cellulosederivative, in another embodiment the SEC is not a cellulose derivativeor a cyclodextrin.

In this aspect of the invention, the alpha-2-adrenergic agonistcomponents are more soluble in the present compositions having, forexample, pH values of about 7 or greater, relative to substantiallyidentical compositions which lack the SECs. In another embodiment, thealpha-2-adrenergic agonist components of the present compositions aremore soluble in neutral or alkaline biological environments into whichthe compositions are administered relative to alpha-2-adrenergic agonistcomponents in similar compositions without the SECs. This latter aspectis particularly true when the alpha-2-adrenergic agonist components aredelivered to their site of action topically.

The alpha-2-adrenergic agonist components used in the present inventioninclude imino-imidazolines, imidazolines, imidazoles, azepines,thiazines, oxazolines, guanidines, catecholamines, biologicallycompatible salts and esters and mixtures thereof. Preferably, thealpha-2-adrenergic agonist components include quinoxaline components.Quinoxaline components include quinoxaline, biologically compatiblesalts thereof, esters thereof, other derivatives thereof and the like,and mixtures thereof. Non-limiting examples of quinoxaline derivativesinclude (2-imidazolin-2-ylamino) quinoxaline,5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline, and biologicallycompatible salts thereof and esters thereof, preferably the tartrate of5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline, and the like andmixtures thereof. Hereinafter, the tartrate of5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline is referred to as“brimonidine tartrate.”

In a preferred embodiment, the alpha-2-adrenergic agonist components,such as those listed above, are selective for the alpha-2A-adrenergicreceptors, alpha-2B-adrenergic receptors and/or alpha-2D-adrenergicreceptors in relation to their activity at one or more other adrenergicreceptor. Preferably, the alpha-2-adrenergic agonist components areselective for the alpha-2A-adrenergic receptors, alpha-2B-adrenergicreceptors and/or alpha-2D-adrenergic receptors in comparison to theiractivity at the alpha-1-adrenergic receptors.

In one embodiment, the alpha-2-adrenergic agonist components are atleast about 30% uncharged in the presently disclosed and claimedcompositions, preferably at least about 50% uncharged. Those of skill inthe art will appreciate that the pKa is the negative log of theionization constant (or the pH at which the compound is 50% ionized),and that a reference in this application to a specific percent of thecompound uncharged (such as, for example, at least 30% or 50% uncharged)is intended to refer to the compound on a stoichiometric basis.

Even more preferably, the soluble alpha-2-adrenergic agonist componentsare also at least about 30% uncharged, or at least about 50% unchargedin the biological environment into which the compositions areadministered.

When the alpha-2-adrenergic agonist components are formulated with anSEC, the SEC may include a non-ionic or polyanionic component. As usedherein, the term “polyanionic component” refers to a chemical entity,for example, an ionically charged species, such as an ionically chargedpolymeric material, which includes multiple discrete anionic charges.Non-ionic SECs may include polyvinyl alcohol (PVA), polyvinylpyrrolidone (povidone), and various gums and other non-ionic agents.

In a preferred embodiment, the SEC is a polyanionic component, which maybe selected from polymeric materials having multiple anionic charges,and mixtures thereof.

Particularly useful polyanionic components are selected from anionicpolymers derived from acrylic acid (meaning to include polymers fromacrylic acid, acrylates and the like and mixtures thereof), anionicpolymers derived from methacrylic acid (meaning to include polymers frommethacrylic acid, methacrylates, and the like and mixtures thereof),anionic polymers derived from alginic acid (meaning to include alginicacid, alginates, and the like and mixtures thereof), anionic polymers ofamino acids (meaning to include polymers of amino acids, amino acidsalts, and the like and mixtures thereof), and the like, and mixturesthereof. Very useful polyanionic components are those selected fromanionic cellulose derivatives and mixtures thereof, especiallycarboxymethyl cellulose and its derivatives.

The polyanionic component preferably is sufficiently anionic to interactwith or otherwise affect or increase the solubility of, thealpha-2-adrenergic components. This interaction preferably is sufficientto render the alpha-2-adrenergic components substantially completelysoluble at therapeutically effective concentrations. The amount of SECin the composition preferably is in the range of about 0.1% (w/v) toabout 30% (w/v), more preferably about 0.2% (w/v) to about 10% (w/v),and even more preferably about 0.2% (w/v) to about 0.6% (w/v).

The compositions may also include carrier components, for example,aqueous liquid carrier components. In one embodiment, the compositionshave pH values of above about 7.0, preferably between about pH 7.0 andabout pH 8.5, more preferably between about 7.2 and about 8.2, even morepreferably between about 7.5 and about 8.0. Furthermore, preferablythese compositions are ophthalmically acceptable.

In another preferred embodiment, a composition is provided whichincludes an alpha-2-adrenergic agonist component in an amount effectiveto provide at least one therapeutic benefit to a patient to whom thecomposition is administered, an anionic cellulose derivative in anamount effective to increase the solubility of the alpha-2-adrenergicagonist component and an aqueous liquid carrier component. Thealpha-2-adrenergic agonist component preferably comprises a tartrate of5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline. The anionic cellulosederivative preferably comprises a carboxymethylcellulose. Theconcentration of the anionic cellulose derivative in the compositionshould be about 0.2% (w/v) to about 0.6% (w/v).

In the preferred embodiments of the composition of the invention, thecomposition contains 5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline or asalt or ester thereof; the concentration of this alpha-2-adrenergicagonist is less than 0.2%; preferably between 0.2% (w/v) and about0.001% (w/v), more preferably about 0.15% (w/v) or less, even morepreferably between 0.15% (w/v) and about 0.001% (w/v), most preferablyabout 0.1% (w/v) or less.

Also, the preferred embodiments of the composition of this inventioncomprise an aqueous solution at neutral or alkaline pH. Preferably thecomposition is about pH 7.0 or greater at room temperature or about 7.2or greater at room temperature, even more preferably about 7.5 orgreater at room temperature, most preferably at about 7.7 or greater atroom temperature.

In a preferred embodiment, the present compositions are ophthalmicallyacceptable, e.g. the compositions do not have deleterious or toxicproperties which could substantially harm the eye of the human or animalto whom the compositions are administered.

In one aspect of the invention, complexes may be formed in thecompositions. In one embodiment, the complexes include monomer unitsderived from at least one quinoxaline component. In a preferredembodiment, the complexes of the present invention are dimers. In aparticularly preferred embodiment, the complexes are complexes,especially dimers, of Brimonidine tartrate.

In another broad aspect of the present invention, compositions areprovided which comprise an alpha-2-adrenergic agonist component and apreservative component in an effective amount to at least aid inpreserving the compositions. Preferably, the preservative componentsinclude oxy-chloro components, such as compounds, ions, complexes andthe like which are biologically acceptable, chemically stable and do notsubstantially or significantly detrimentally affect thealpha-2-adrenergic agonist component in the compositions or the patientsto whom the compositions are administered. Such compositions preferablyare substantially free of cyclodextrins in the compositions or thepatients to whom the compositions are administered.

Any feature or combination of features described herein are includedwithin the scope of the present invention provided that the featuresincluded in any such combination are not mutually inconsistent as willbe apparent from the context, this specification, and the knowledge ofone of ordinary skill in the art. Whenever numerical ranges areindicated herein, they should be understood as disclosing each and everyindividual value that fall within the range, i.e. that they are a mereabbreviation of listing all these values.

Additional advantages and aspects of the present invention are apparentin the following detailed description and claims.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a graph of soluble brimonidine tartrate in aqueous solution atroom temperature plotted versus pH at various carboxymethylcelluloseconcentrations.

DETAILED DESCRIPTION OF THE INVENTION

Therapeutically effective compositions comprising alpha-2-adrenergicagonist components are provided. These compositions provide theadvantage of being formulated at neutral or alkaline pH, thus providinga dosage of the active agent in a substantially uncharged, more lipidsoluble form. Since the alpha-2-adrenergic agonist components are moreable to cross cellular membranes the compositions of the presentinvention maintain or increase efficacy relative to a compositionformulated at acid pH.

Each aspect of the compositions of the invention is necessarilytherapeutically effective; a composition which is not therapeuticallyeffective is not intended to fall within the ambit of any claim hereof.By “therapeutically effective” is meant that the composition is able toexert a statistically significant medically beneficial effect when usedas prescribed or directed, as compared to a placebo. Thus, a compositionprescribed for use to lower intraocular pressure is and shall beintended to refer to a composition having a statistically significantocular hypotensive effect when used as directed.

In one embodiment, the present invention envisages a composition, suchas a topical ophthalmic composition, comprising an alpha-2-adrenergicagonist component formulated in aqueous solution at a pH such that thealpha adrenergic component is at least 30%, at least 40%, at least 50%or at least 60% uncharged.

In a particularly preferred embodiment, the invention is directed to acomposition comprising 5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline,or salts thereof, wherein the solution is formulated at a concentrationof less than 0.2% (w/v). Preferably the active ingredient is present inthe composition at a concentration of preferably between 0.2% (w/v) andabout 0.001% (w/v), more preferably about 0.15% (w/v) or less, even morepreferably between 0.15% (w/v) and about 0.001% (w/v), most preferablyabout 0.1% (w/v) or less.

As a further preferred aspect of this embodiment of the invention, the5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline, or salt thereof, is inaqueous solution at a pH of greater than about 7.0 at room temperatureor about 7.2 or greater at room temperature, even more preferably about7.5 or greater at room temperature, most preferably at about 7.7 orgreater at room temperature.

In another embodiment, the alpha-2-adrenergic agonist components in thepresent compositions are made more soluble, particularly at neutral toalkaline pH values, and may be more effectively utilized as therapeuticagents. The SECs employed in the present compositions may be effectivein the solubilization of charged alpha-2-adrenergic agonist components,uncharged alpha-2-adrenergic agonist components or both. The presentcompositions include liquid carrier components and have thecharacteristics of liquid, for example, aqueous liquid, solutions.

Alpha-2-adrenergic agonist components have a stimulatory activitydirected towards at least one of the alpha 2 receptor subtypes alpha 2A,alpha 2B or alpha 2C. Preferably, the activity at such subtype(s) is atleast 10 fold greater than at any alpha 1 adrenergic receptor subtype.Even more preferably, the activity at an alpha 2 receptor is at least 50fold greater, or at least 100 fold greater or at least 1000 fold greaterthan at any alpha 1 receptor. Exemplary alpha-2-agonists include,without limitation, xylazine, detomidine, medetomidine, clonidine,brimonidine, tizanidine, lofexidine, guanfacine, guanabenz acetate, anddexmedetomidine.

The alpha-2-adrenergic agonist components are soluble in the presentcompositions at pH values greater than 7. In one embodiment, the presentconcentrations contain the alpha adrenergic agonist components at ornearly at their aqueous solubility limit at room temperature andmaintain comparable efficacy to higher concentrations of the alphaadrenergic agonist components in a similar composition at a pH of 7 orbelow.

In one preferred embodiment, the alpha-2-adrenergic agonist componentsare combined with at least one SEC in the presently claimedcompositions, and therefore have increased solubility in the presentcompositions at pH values greater than 7, such as, without limitation,about pH 7.2, about pH 7.4, about pH 7.7, and about pH 8.0, as comparedto identical alpha-2-adrenergic agonist components, at comparableconcentrations, in compositions lacking the SECs.

A preferred composition comprises about 0.1% (w/v) brimonidine at a pHabout 7.7. Even more preferably, such a composition also comprises anSEC. The SEC may be selected from any SEC, but preferred SECs includecarboxymethyl cellulose, polyvinyl alcohol, or polyvinyl pyrrolidone.

In another embodiment, the alpha-2-adrenergic agonist components haveincreased solubility in the present compositions at pH values in therange of about 7 to about 10 and, as compared to identicalalpha-2-adrenergic agonist components in similar compositions, atcomparable concentrations, without the SECs. Even more preferably thealpha-2-adrenergic agonist components in the compositions of the presentinvention have such increased solubility at pH values of above about7.0, preferably between about pH 7.0 and about pH 8.5, more preferablybetween about 7.2 and about 8.2, even more preferably between about 7.5and about 8.0, or at about pH 7.7.

Without wishing to be limited by any theory or mechanism of operation,it is believed that solubilized alpha-2-adrenergic agonist componentsare better able to cross lipid membranes relative to unsolubilizedalpha-2-adrenergic agonist components. Moreover, it is also believedthat an uncharged alpha-2-adrenergic agonist component is better able tocross a lipid membrane than one which is charged.

In one embodiment, the SECs are capable of solubilizing thealpha-2-adrenergic agonist components in the biological environmentsinto which they are introduced at therapeutically effectiveconcentrations. Preferably, the biological environments into which thepresent compositions are introduced have pH values ranging from about 7to about 9. For example, a composition comprising a SEC and analpha-2-adrenergic agonist component may be topically administered tothe surface of an eye, which has a pH of about 7, wherein thealpha-2-adrenergic agonist component is substantially soluble at theadministered area. Furthermore, the soluble alpha-2-adrenergic agonistcomponents at the administered area will diffuse more readily throughbiological lipid membranes than alpha-2-adrenergic agonist componentswhich are not soluble, whether in the presence of SECs or otherwise.Maintaining solubility of alpha-2-adrenergic agonist components inaqueous solution preferably reduces irritation to sensitive tissues incontact or interacting with the alpha-2-adrenergic agonist components.

Of course, the soluble alpha-2-adrenergic agonist components in thecompositions hereby disclosed and claimed must be capable of beingdelivered at a therapeutically effective concentration. While it isclearly possible to make a solution containing vanishingly smallconcentrations of soluble alpha-2-adrenergic agonist components, such asolution is not therapeutically useful unless it is effective to confera benefit to the mammal who receives it. Preferably, the currentcompositions are capable of delivering a therapeutic effectsubstantially equal to, or greater than, that provided by a formulationof the same alpha-2-adrenergic agonist component at a pH less than 7.0.Even more preferably, the current compositions are capable of deliveringa therapeutic effect substantially equal to, or greater than, thatprovided by a formulation of the same alpha-2-adrenergic agonistcomponent at a pH less than 7.0, and at a lower concentration of theactive agent than in the lower pH formulation.

In one preferred embodiment the presently useful alpha-2-adrenergicagonist components are chosen to benefit from and be stabilized orsolublized by the presence of the SECs. In this embodiment, thealpha-2-adrenergic agonist components are provided with increasedapparent solubility preferably increased apparent water solubility, bythe presence of the SECs.

Examples of alpha-2-adrenergic agonist components include moleculescontaining amines. Preferably, the alpha-2-adrenergic agonist componentsare amine-containing molecules with pKa's of greater than about 7, morepreferably about 7 to about 9.

Alpha-2-adrenergic agonist components include alpha-2-adrenergicagonists. As used herein, the term alpha-2 adrenergic agonist includeschemical entities, such as compounds, salts, esters, ions, complexes andthe like, that bind to, and activate, one or more of the alpha 2Aadrenergic receptor, the alpha 2B adrenergic receptor and alpha 2Cadrenergic receptor. When stimulated, these G-protein coupled receptorsperform a number of cell signaling functions; one or more may beinvolved in, for example, inhibiting the presynaptic release of theneurotransmitter norepinepherine. While not wishing to be bound bytheory, it is thought that stimulation of one or more of the alpha 2receptor subtypes results in the suppression of calcium influx into thetarget neuron, thus inhibiting neurotransmitter release. This inhibitionof norepinpherine in presynaptic neurons appears to be involved inanalgesia by inhibiting the generation or propagation of the painresponse.

While the alpha 2 receptors are found predominantly in a presynapticsite, alpha 2 receptors can also be found in post- and extrasynapticlocations and in peripheral and CNS neurons.

The alpha-2 adrenergic agonists of the invention bind to the alpha-2adrenergic receptors, and are able to cause a decrease or inhibition ofthe release of neuronal norepinephrine at the presynaptic sites inaffected cells. Additionally, they may work on alpha-2 adrenergicreceptors postsynaptically, for example, by inhibiting beta-adrenergicreceptor-stimulated formation of cyclic AMP.

Alpha-2 adrenergic agonists also include compounds that haveneuroprotective activity. For example,5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline is an alpha-2-adrenergicagonist which has a neuroprotective activity. The mechanism orneuroprotection is still not completely known.

Without limiting the invention to the specific groups and compoundslisted, the following is a list of representative alpha-2 adrenergicagonists useful in this invention: imino-imidazolines, includingclonidine, apraclonidine; imidazolines, including naphazoline,oxymetazoline, tetrahydrozoline, and tramazoline; imidazoles, includingdetomidine, medetomidine, and dexmedetomidine; azepines, including B-HT920 (6-allyl-2-amino-5,6,7,8 tetrahydro-4H-thiazolo[4,5-d]-azepine andB-HT 933; thiazines, including xylazine; oxazolines, includingrilmenidine; guanidines, including guanabenz and guanfacine;catecholamines; and the like and esters, salts and derivatives thereof.

Particularly useful alpha-2-adrenergic agonists include quinoxalinecomponents. In one embodiment, the quinoxaline components includequinoxaline, derivatives thereof and mixtures thereof. Preferably, thederivatives of quinoxaline include (2-imidazolin-2-ylamino) quinoxaline.More preferably, the derivatives of quinoxaline include5-halide-6-(2-imidazolin-2-ylamino) quinoxaline. The “halide” of the5-halide-6-(2-imidazolin-2-ylamino) quinoxaline may be a fluorine, achlorine, an iodine, or preferably, a bromine, to form5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline. Even more preferably,the derivatives of quinoxaline to be used in accordance with thisinvention include a tartrate of 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline, or brimonidine tartrate.

Other useful quinoxaline derivatives are well known. For example, usefulderivatives of a quinoxaline include the ones disclose by Burke et alU.S. Pat. No. 5,703,077. See also Danielwicz et al U.S. Pat. No.3,890,319. Each of the disclosures of Burke et al and Danielwicz et alis incorporated in its entirety by reference herein.

The quinoxalines and derivatives thereof, for example brimonidinetartrate, are amine-containing and preferably have pKa's of greater than7, preferably about 7.5 to 9. Analogs of the foregoing compounds thatfunction as alpha-2 adrenergic agonists also are specifically intendedto be embraced by the invention.

Preferably, the alpha-2-adrenergic agonists of the present invention,are effective in activating alpha-2A-adrenergic receptors,alpha-2B-adrenergic receptors and/or alpha-2C adrenergic receptors.

In one embodiment, the alpha-2-adrenergic agonist components are atleast about 30% uncharged in the presently disclosed and claimedcompositions, preferably at least about 50% uncharged. Those of skill inthe art will appreciate that the pKa is the negative log of theionization constant (or the pH at which the compound is 50% ionized),and that a reference in this application to a specific percent of thecompound uncharged (such as, for example, at least 30% or 50% uncharged)is intended to refer to the compound on a stoichiometric basis.

Preferably, the soluble alpha-2-adrenergic agonist components of thepresent formulations are at least about 30% uncharged, or at least about50% uncharged in the biological environment into which the compositionsare administered.

Without wishing to be limited by any theory or mechanism of action, itis believed that the uncharged forms of the present alpha 2 adrenergiccompounds facilitate their permeability across membrane lipid bilayers.

In those embodiments involving an SEC, any suitable SEC (or combinationof SECs) may be employed in accordance with the present invention. Inone embodiment, the SECs include uncharged SECs, such as, withoutlimitation, pyrrolidone components, polyvinyl alcohol (PVA), unchargedcellulose derivatives, Pemulen, carbomers, Carbopols and the like.Examples of pyrrolidone components are polyvinylpyrrolidones (povidone)and derivatives thereof. In a further embodiment, the SECs includepolyanionic components. The useful polyanionic components include, butare not limited to, those materials which are effective in increasingthe apparent solubility, preferably water solubility, of poorly solublealpha-2-adrenergic agonist components and/or enhance the stability ofthe alpha-2-adrenergic agonist components and/or reduce unwanted sideeffects of the alpha-2-adrenergic agonist components. Furthermore, thepolyanionic component is preferably ophthalmically acceptable fortopical treatment at the concentrations used. Additionally, thepolyanionic component preferably includes three (3) or more anionic (ornegative) charges. In the event that the polyanionic component is apolymeric material, it is preferred that each of the repeating units ofthe polymeric material include a discrete anionic charge. Particularlyuseful anionic components are those which are water soluble, forexample, soluble at the concentrations and pH values used in thepresently useful liquid aqueous media, such as a liquid aqueous mediumcontaining the alpha-2-adrenergic components.

The polyanionic component is preferably sufficiently anionic to form anionic or other electrostatic interaction with those charged or polarmoieties of the alpha-2-adrenergic agonist component. Such interactionis believed to be desirable to solubilize certain formulations of thealpha-2-adrenergic agonist component and/or to maintain suchalpha-2-adrenergic agonist component soluble in the carrier component,for example a liquid medium.

Polyanionic components also include one or more polymeric materialshaving multiple anionic charges. Examples include:

metal carboxymethylstarchs

metal carboxymethylhydroxyethylstarchs

hydrolyzed polyacrylamides and polyacrylonitriles

heparin

homopolymers and copolymers of one or more of:

-   -   acrylic and methacrylic acids    -   metal acrylates and methacrylates    -   alginic acid    -   metal alginates    -   vinylsulfonic acid    -   metal vinylsulfonate    -   amino acids, such as aspartic acid, glutamic acid and the like    -   metal salts of amino acids    -   p-styrenesulfonic acid    -   metal p-styrenesulfonate    -   2-methacryloyloxyethylsulfonic acids    -   metal 2-methacryloyloxethylsulfonates    -   3-methacryloyloxy-2-hydroxypropylsulonic acids    -   metal 3-methacryloyloxy-2-hydroxypropylsulfonates    -   2-acrylamido-2-methylpropanesulfonic acids    -   metal 2-acrylamido-2-methylpropanesulfonates    -   allylsulfonic acid    -   metal allylsulfonate and the like.

By “metal” is meant alkali and alkaline earth metals such as Na, K, Caand the like.

In another embodiment, the polyanionic components include anionicpolysaccharides which tend to exist in ionized forms at higher pHs, forexample, pH's of about 7 or higher. The following are some examples ofanionic polysaccharides which may be employed in accordance with thisinvention.

Polydextrose is a randomly bonded condensation polymer of dextrose whichis only partially metabolized by mammals. The polymer can contain aminor amount of bound sorbitol, citric acid, and glucose. Chondroitinsulfate also known as sodium chondroitin sulfate is a mucopolysaccharidefound in every part of human tissue, specifically cartilage, bones,tendons, ligaments, and vascular walls. This polysaccharide has beenextracted and purified from the cartilage of sharks.

Carrageenan is a linear polysaccharide having repeating galactose unitsand 3,6 anhydrogalactose units, both of which can be sulfated ornonsulfated, joined by alternating 1-3 and beta 1-4 glycosidic linkages.Carrageenan is a hydrocolloid which is heat extracted from severalspecies of red seaweed and irish moss.

Maltodextrins are water soluble glucose polymers which are formed by thereaction of starch with an acid and/or enzymes in the presence of water.

Other anionic polysaccharides found useful in the present invention arehydrophilic colloidal materials and include the natural gums such asgellan gum, alginate gums, i.e., the ammonium and alkali metal salts ofalginic acid and mixtures thereof. In addition, chitosan, which is thecommon name for deacetylated chitin, is useful. Chitin is a naturalproduct comprising poly-(N-acetyl-D-glucosamine). Gellan gum is producedfrom the fermentation of Pseudomonas elodea to yield an extracellularheteropolysaccharide. The alginates and chitosan are available as drypowders from, e.g., Protan, Inc., Commack, N.Y. Gellan gum can bepurchased from, e.g., the Kelco Division of Merk & Co., Inc., San Diego,Calif.

Generally, the alginates can be any of the water-soluble alginatesincluding the alkali metal alginates, such as sodium, potassium,lithium, rubidium and cesium salts of alginic acid, as well as theammonium salt, and the soluble alginates of an organic base such asmono-, di-, or tri-ethanolamine alginates, aniline alginates, and thelike. Generally, about 0.2% to about 1% by weight and, preferably, about0.5% to about 3.0% by weight of gellan, alginate or chitosan ionicpolysaccharides, based upon the total weight of the composition, areused to obtain the gel compositions of the invention.

In one embodiment, the anionic polysaccharides are cyclized. Morepreferably, the cyclized anionic polysaccharides include less than tenmonomer units. Even more preferably, the cyclized polysaccharidesinclude less than six monomer units.

A particularly useful group of cyclized anionic polysaccharides includesthe cyclodextrins. Examples of the cyclodextrin group include, but arenot limited to: α-cyclodextrin, derivatives of α-cyclodextrin,β-cyclodextrin, derivatives of β-cyclodextrin, γ-cyclodextrin,derivatives of γ-cyclodextrin, carboxymethyl-β-cyclodextrin,carboxymethyl-ethyl-β-cyclodextrin, diethyl-β-cyclodextrin,dimethyl-β-cyclodextrin, methyl-β-cyclodextrin, randommethyl-β-cyclodextrin, glucosyl-β-cyclodextrin, maltosyl-β-cyclodextrin,hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin,sulfobutylether-β-cyclodextrin, and the like and mixtures thereof.Sulfobutylether-β-cyclodextrin is a preferred cyclized anionicpolyasaccharide in accordance with the present invention. It isadvantageous that the SECs employed in this invention, including theabove mentioned cyclodextrins, be formulated at so as to be non-toxic tothe mammal (including to humans) at the concentration employed.

As used herein, the term “derivative(s)”, as it relates to acyclodextrin, means any substituted or otherwise modified compound whichhas the characteristic chemical structure of a cyclodextrin sufficientlyto function as a cyclodextrin component, for example, to enhance thesolubility and/or stability of active components and/or reduce unwantedside effects of the active components and/or to form inclusive complexeswith active components, as described herein.

Although cyclodextrins and/or their derivatives may be employed as SECs,one embodiment of the invention may include SECs other thancyclodextrins and/or their derivatives.

A particularly useful and preferred class of polyanionic componentincludes anionic cellulose derivatives. Anionic cellulose derivativesinclude metal carboxymethyl celluloses, metal carboxymethyl hydroxyethylcelluloses and hydroxypropyl methyl celluloses and derivatives thereof.

The present polyanionic components often can exist in the unchargedstate, for example in the solid state, in combination with a counterion; in particular, a plurality of discrete cations approximately equalin number to the number of discrete anionic charges of the SEC so thatthe polyanionic component is electrically neutral when it possesses acharge.

Since the polyanionic components are preferably ophthalmicallyacceptable, it is preferred that the metal associated with the unionizedpolyanionic component be ophthalmically acceptable in the concentrationsused. Particularly useful metals include the alkali metals, for example,sodium and potassium, the alkaline earth metals, for example, calciumand magnesium, and mixtures thereof.

Sodium is a very useful metal capable of acting as a counter ion in theunionized polyanionic component. Polyanionic components which, in theunionized states, are combined with cations other than H⁺ and metalcations can be employed in the present invention.

In those embodiments of the present invention that involve the use ofSECs, the amount of SEC is not of critical importance so long assolubility at the alpha-2-adrenergic agonist component is at leastsomewhat increased and is present in a biologically acceptable amount.Such amount should be effective to perform the desired function orfunctions in the present composition and/or after administration to thehuman or animal. In one embodiment, the amount of SEC, preferably thepolyanionic component, is sufficient to assist in solubilizing a majoramount, and more preferably substantially all, of the alpha-2-adrenergicagonist component in the present composition. In one useful embodiment,the amount of polyanionic component in the present composition is in therange of about 0.1% to about 30% (w/v) or more of the composition.Preferably, the amount of polyanionic component is in the range of about0.2% (w/v) to about 10% (w/v). More preferably, the amount ofpolyanionic component is in the range of about 0.2% (w/v) to about 0.6%(w/v).

Even more preferably, the polyanionic component iscarboxymethylcellulose and is present in the composition in the range ofabout 0.2% (w/v) to about 0.6% (w/v). A particularly usefulconcentration of carboxymethylcellulose in the present compositions isabout 0.5%.

In one embodiment, the SECs, for example a carboxymethylcellulose,assist in solubilizing the alpha-2-adrenergic agonist components in thecompositions. Although the SECs are capable of aiding in thesolubilization of ionized alpha-2-adrenergic agonist components, it ispreferable that SECs used in this aspect of the invention assist in thesolubilization of alpha-2-adrenergic agonist components at neutral oralkaline pH. For example, in one embodiment, carboxymethylcellulose mayhelp solubilize ionized alpha-2-adrenergic agonist components. Inanother embodiment, carboxymethylcellulose may help solubilizesubstantially uncharged population of alpha-2-adrenergic agonistcomponents. In a preferred embodiment, the carboxylmethylcellulose helpssolubilize ionized brimonidine tartrate in the compositions. Morepreferably, the carboxylmethylcellulose helps solubilize a substantiallyuncharged population of brimonidine tartrate in the compositions.

The compositions of the present invention may also include preservativecomponents or components which assist in the preservation of thecomposition. In a preferred embodiment the claimed compositions containsat least one preservative component selected so as to be effective andefficacious as preservatives in the present compositions, that is in thepresence of polyanionic components, and preferably have reduced toxicityand more preferably substantially no toxicity when the compositions areadministered to a human or animal.

Preferably, the present preservative components or components whichassist in the preservation of the composition, preferably thealpha-2-adrenergic agonist components therein, are effective inconcentrations of less than about 1% (w/v) or about 0.8% (w/v) and maybe 500 ppm (w/v) or less, for example, in the range of about 10 ppm(w/v) or less to about 200 ppm (w/v). Preservative components inaccordance with the present invention preferably include, but are notlimited to, those which form complexes with the polyanionic component toa lesser extent than does benzalkonium chloride.

Very useful examples of the present preservative components include, butare not limited to oxidative preservative components, for example andwithout limitation, oxidative preservatives such as oxy-chloro andoxy-borate components, peroxides, persalts, peracids, and the like, andmixtures thereof. Specific examples of oxy-chloro components useful aspreservatives in accordance with the present invention includehypochlorite components, for example hypochlorites; chlorate components,for example chlorates; perchlorate components, for example perchlorates;and chlorite components. Examples of chlorite components includestabilized chlorine dioxide (SCD), metal chlorites, such as alkali metaland alkaline earth metal chlorites, and the like and mixtures therefor.Technical grade (or USP grade) sodium chlorite is a very usefulpreservative component. The exact chemical composition of many chloritecomponents, for example, SCD, is not completely understood. Themanufacture or production of certain chlorite components is described inMcNicholas U.S. Pat. No. 3,278,447, which is incorporated in itsentirety herein by reference. Specific examples of useful SCD productsinclude that sold under the trademark Dura Klor by Rio Linda ChemicalCompany, Inc., and that sold under the trademark Anthium Dioxide byInternational Dioxide, Inc. An especially useful SCD is a product soldunder the trademark Purite™ by Allergan, Inc.

Other examples of oxidative preservative components includes peroxycomponents. For example, trace amounts of peroxy components stabilizedwith a hydrogen peroxide stabilizer, such as diethylene triaminepenta(methylene phosphonic acid) or 1-hydroxyethylidene-1,1-diphosphonicacid, may be utilized as a preservative for use in components designedto be used in the ocular environment. Also, virtually any peroxycomponent may be used so long as it is hydrolyzed in water to producehydrogen peroxide. Examples of such sources of hydrogen peroxide, whichprovide an effective resultant amount of hydrogen peroxide, includesodium perborate decahydrate, sodium peroxide and urea peroxide. It hasbeen found that peracetic acid, an organic peroxy compound, may not bestabilized utilizing the present system. See, for example, Martin et alU.S. Pat. No. 5,725,887, the disclosure of which is incorporated in itsentirety herein by reference.

Preservatives other than oxidative preservative components may beincluded in the compositions. The choice of preservatives may depend onthe route of administration. Preservatives suitable for compositions tobe administered by one route may possess detrimental properties whichpreclude their administration by another route. For nasal and ophthalmiccompositions, preferred preservatives include, without limitation,quaternary ammonium compounds, in particular the mixture of alkyl benzyldimethyl ammonium compounds and the like known generically as“benzalkonium chloride”, the mixture comprising decyltrimethylmmoniumbromide, dodecyltrimethylmmonium bromide and tetradecyltrimethylmmoniumbromide termed “cetrimide”, BDB, and the preservative polyquaternium-1(marketed under the trade name Polyquad®), and biguanide preservatives,such as polyhexamethylene biguanide (“PHMB”).

For compositions to be administered by inhalation, however, thepreferred preservative is chlorbutol and the like. Other preservativeswhich may be used, especially for compositions to be administeredrectally, include alkyl esters of p-hydroxybenzoic acid and mixturesthereof, such as the mixture of methyl, ethyl, propyl, butyl esters andthe like which is sold under the trade name “Nipastat.”

In another broad aspect of the present invention, compositions areprovided which comprise an alpha-2-adrenergic agonist component, apreservative component in an effective amount to at least aid inpreserving, preferably in an amount effective to preserve, thecompositions and a liquid carrier component. Preferably, thepreservative components include oxy-chloro components, or PHMB. Suchcompounds must be effective at preventing the growth of gram positivebacteria, gram negative bacteria, or fungi and preferably be such thatthey (1) do not substantially or significantly detrimentally affect thealpha-2-adrenergic agonist components in the compositions or thepatients to whom the compositions are administered, and (2) aresubstantially biologically acceptable and chemically stable. Suchcompositions in accordance with the present invention comprise analpha-2-adrenergic agonist component, an oxy-chloro component, aquaternary ammonium compound, or a biguanide such as PHMB, and a liquidcarrier component, and preferably are substantially free ofcyclodextrins.

The carrier components useful in the present invention are selected tobe non-toxic and have no substantial detrimental effect on the presentcompositions, on the use of the compositions or on the human or animalto whom the compositions are administered.

In one embodiment, the carrier component is a liquid carrier. In apreferred embodiment, the carrier component is a liquid aqueous carriercomponent. A particularly useful aqueous liquid carrier component isthat derived from saline, for example, a conventional saline solution ora conventional buffered saline solution. The aqueous liquid carrierpreferably has a pH in the range of about 6 to about 9 or about 10, morepreferably about 6 to about 8, and still more preferably about 7.5. Theliquid medium preferably has an ophthalmically acceptable tonicitylevel, for example, of at least about 200 mOsmol/kg, more preferably inthe range of about 200 to about 400 mOsmol/kg. In an especially usefulembodiment, the osmolality or tonicity of the carrier component issubstantially isotonic with reference to the tonicity of the fluids ofthe surface of the eye, in particular the human eye.

In one embodiment, the carrier components containing the SECs and thealpha-2-adrenergic agonist components may have viscosities of more thanabout 0.01 centipoise (cps) at 25° C., preferably more than about 1 cpsat 25° C., even more preferably more than about 10 cps at 25° C. In apreferred embodiment, the composition has a viscosity of about 50 cps at25° C. and comprises a conventional buffer saline solution, acarboxymethylcellulose and brimonidine tartrate.

In order to insure that the pH of the aqueous liquid carrier component,and thus the pH of the composition, is maintained within the desiredrange, the aqueous liquid carrier component may include at least onebuffer component. Although any suitable buffer component may beemployed, it is preferred to select a buffer not capable of evolving asignificant amount of gas, such as chlorine dioxide or CO₂. It ispreferred that the buffer component be inorganic. Alkali metal andalkaline earth metal salt buffer components are advantageously used inthe present invention.

Any suitable ophthalmically acceptable tonicity adjusting component maybe employed, provided that such component or components are compatiblewith the other ingredients of the liquid aqueous carrier component anddo not have deleterious or toxic properties which could harm the humanor animal to whom the present compositions are administered. Examples ofuseful tonicity components include sodium chloride, potassium chloride,mannitol, dextrose, glycerin, propylene glycol and mixtures thereof. Inone embodiment, the tonicity component is selected from inorganic saltsand mixtures thereof.

The present compositions may conveniently be presented as solutions orsuspensions in aqueous liquids or non-aqueous liquids, or asoil-in-water or water-in-oil liquid emulsions. The present compositionsmay include one or more additional ingredients such as diluents,flavoring agents, surface active agents, thickeners, lubricants, and thelike, for example, such additional ingredients which are conventionallyemployed in compositions of the same general type.

The present compositions, if in the form of aqueous suspensions, mayinclude excipients suitable for the manufacture of aqueous suspensions.Such excipients are suspending agents, without limitation includingsodium alginate, gum tragacanth and gum acacia. Dispersing or wettingagents may include a naturally occurring phosphatide, for example,lecithin, or condensation products of ethylene oxide with long chainaliphatic alcohols, for example, heptadecaethyleneoxycetanol, orcondensation products of ethylene oxide with partial esters derived fromfatty acids and a hexitol such as polyoxyethylene sorbitol mono-oleate,or condensation products of ethylene oxide with partial esters derivedfrom fatty acids and hexitol anhydrides, for example, polyoxyethylenesorbitan mono-oleate, and the like and mixtures thereof. Aqueoussuspensions of this aspect of the present invention may also contain oneor more coloring agents, one or more flavoring agents and one or moresweetening agents, such as sucrose, saccharin, and the like and mixturesthereof.

If the present compositions are in the form of oily suspensions they maybe formulated in a vegetable oil, for example, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. Suchsuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation.

The present compositions may alternatively be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample, olive oil or arachis oil, or a mineral oil, for example, liquidparaffin, and the like and mixtures thereof. Suitable emulsifying agentsmay be naturally-occurring gums, for example, gum acacia or guntragacanth, naturally-occurring phosphatides, for example, soya beanlecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan mono-oleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan mono-oleate. The emulsions may also containsweetening and flavoring agents.

The present compositions, if in the form of syrups and elixirs, may beformulated with sweetening agents, for example, as described elsewhereherein. Such formulations may also contain a demulcent, and flavoringand coloring agents.

The specific dose level for any particular human or animal depends upona variety of factors including the activity of the active componentemployed, the age, body weight, general health, sex, diet, time ofadministration, pH of the formulation, route of administration, rate ofexcretion, drug combination and the severity of the particular conditionundergoing therapy. For 5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline,a therapeutically effective dose in the present compositions isdelivered at a concentration of less than 0.2% (w/v), such as about0.15% (w/v) or about 0.1% (w/v) or less. The pH of such compositions isgreater than 7.0; in one aspect the dose is about 0.15% and the pH isabout 7.2; in another aspect the dose is about 0.1% and the pH is about7.7.

In one aspect of the invention, complexes are formed in the presentcompositions. In one embodiment, the complexes include at least onemonomer unit of a quinoxaline component. Examples of quinoxalinecomponents include quinoxaline, (2-imidazolin-2-ylamino) quinoxaline,5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline, salts thereof, estersthereof, other derivatives thereof, and the like and mixtures thereof.For example, in one embodiment, a complex of the present invention mayinclude a conjugation of 5-bromo-6-(2-imidazolin-2-ylamino) quinoxalinemonomer units. In another embodiment, the complex may include aconjugation of 5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline monomerunits and brimonidine tartrate monomer units.

In a preferred embodiment of this aspect, the complexes of the presentinvention are dimers. For example, a dimer in accordance with thepresent invention may include a quinoxaline and a5-bromo-6-(2-imidazolin-2-ylamino) quinoxaline. Preferably, a dimer inaccordance with the present invention includes two trimonidine tartratemonomer units.

Without wishing to limit this aspect of the invention to any theory ormechanism of operation, it is believed that a peroxide forming agent orstrong oxidizing agent such as the oxidative preservative components,for example oxy-chloro components, peroxides, persalts, peracids, andthe like, and mixtures thereof may facilitate the formation of thecomplexes, preferably complexes of alpha-2-adrenergic agonistcomponents. For example, dimers of brimonidine tartrate monomer unitsare believed to be formed in the presence of chlorites, preferablystabilized chlorine dioxide.

Furthermore, it is believed that the interactions between the monomerswhich serve to hold the monomers or monomer subunits together to form acomplex, preferably an oligomer and more preferably a dimer, mayinclude, but not limited to, covalent bonding, ionic bonding,hydrophobic bonding, electrostatic bonding, hydrogen bonding, otherchemical and/or physical interactions, and the like and combinationsthereof. Such complexes may disassociate in liquid, for example, aqueousliquid, media. In one embodiment, the monomers or monomer subunits areheld together by other than covalent bonding. In one embodiment, themonomers or monomer subunits are held together by electrostatic bondingor forces.

The following non-limiting examples illustrate certain aspects of thepresent invention.

Example 1

Brimonidine tartrate has a pKa of about 7.78. The pH-solubility profileof brimonidine tartrate in an aqueous formulation (Ophthalmic Solution)was established in the pH range of about 5 to about 8 at 23° C. Table 1.It will be understood that concentrations of adrenergic agonists otherthan those shown may be used in the compositions of the presentinvention, so long as they have therapeutic activity. Likewise, thetemperature may be varied somewhat, for example, solubility curves maybe performed at room temperature.

The formulation vehicle was prepared by first dissolving polyvinylalcohol (PVA) in water. The PVA was added to approximately ⅓ of therequired total amount of purified water with constant stirring. Theslurry was stirred for 20-30 minutes and then heated to 80-95° C. withconstant stirring. The mixture was removed from the heat source within 1hour after having reached the temperature of 80-90° C. and stirred foran additional 10 minutes to ensure homogeneity (Part I). The otheringredients of the Ophthalmic Solution, except for brimonidine tartrate,were dissolved in a separate container with an additional ⅓ of therequired total amount of purified water (Part II). The PVA mixture (PartI) was then quantitatively transferred to Part II using several rinsevolumes of purified water. The solution was adjusted to final volumewith purified water without pH adjustment.

Brimonidine tartrate was weighed and transferred to a 10 mL test tubecontaining 5 mL of the formulation vehicle described above. The pH ofeach sample was then adjusted to a desired value using dilute sodiumhydroxide and/or dilute hydrochloric acid. The samples were placed in arack on a stir plate and stirred at high speed to achieve uniform mixingfor 2 days; a partition was placed between the rack and the stir plateto prevent any heat diffusion from the stir plate to the samples. Thetemperature of the laboratory was monitored throughout the study and wasfound to be 23±1° C.

At the end of two days of stirring, the pH value of each sample wasmeasured, and then approximately 1 mL of each sample was placed in amicro centrifuge tube (polypropylene) and centrifuged at 4,000 rpm for10 minutes. The supernatant was filtered through a 1 μm filter unit(Whatman, 13 mm, PTFE). The first 3-4 drops of the filtrate werediscarded; the rest of the filtrate was received and dilutedquantitatively with HPLC mobile phase. The dilute sample was theninjected directly on the HPLC column (Dupont Zorbax, 250 mm×4.6 mm, 5μm) for brimonidine tartrate assay in order to quantify the amount ofbrimonidine tartrate. A control of 0.5% brimonidine tartrate wasprepared in the same formulation vehicle at pH 6.3-6.5 and assayedbefore (untreated) and after (treated) centrifugation and filtration.This was done to evaluate the potential loss of brimonidine tartrate inthese two steps of the sample preparation.

To ensure reproducibility, the study was repeated on consecutive days.

TABLE I 0.5% Brimonidine tartrate in Ophthalmic Solution. IngredientPercent (w/v) Brimonidine tartrate 0.50 Benzalkonium Chloride, NF 0.0050Polyvinyl Alcohol, USP 1.4 Sodium Chloride, USP 0.66 Sodium Citrate,dihydrate, USP 0.45 Hydrochloric Acid, NF or 5-8 Sodium Hydroxide, NFfor pH adjustment Purified Water, USP QS

The solubility data for brimonidine tartrate in the formulation vehiclesare presented in Table II. The results show that the solubility ofbrimonidine tartrate is highly pH-dependent and spans more than twoorders of magnitude over the pH range of 5-8. The solubility decreasessharply as the pH increases. The results for the treated and untreatedcontrols are very close, suggesting that centrifugation and filtrationdoes not cause any significant loss of brimonidine tartrate. The twosolubility profiles obtained on consecutive days agree with each other.

TABLE II Solubility Of Brimonidine Tartrate In The Ophthalmic SolutionOver pH Range Of 5 To 8. STUDY 1 STUDY 2 Sample pH^(a) Solubility^(e)pH^(a) Solubility^(e) 1 5.55> 16.44^(b) 5.50> 20.06^(b) 2 5.92 13.265.92 16.08 3 6.14 3.04 6.06 5.01 4 6.57 0.755 6.90 0.319 5 7.00 0.2697.40 0.119 6 7.45 0.117 7.77 0.063 7 7.83 0.062 7.86 0.058 8 — — 7.880.054 Control/ — 0.486^(c) — — (untreated) Control/ — 0.484^(d) — —(treated) ^(a)Measured after stirring for two-days before samplewithdrawal for centrifugation and filtration. ^(b)Represents theoreticalconcentration based on sample weight. The sample solution was clearindicating that all of the brimonidine tartrate had dissolved.^(c)Concentration of brimonidine tartrate in control beforecentrifugation and filtration step. ^(d)Concentration of brimonidinetartrate in control after centrifugation and filtration step. ^(e)mgml⁻¹

Example 2

The effect of pH on the solubility of brimonidine tartrate in liquidformulations with and without SECs was determined. Particularly, theeffect of the presence or absence of various concentrations of anexemplary SEC, sodium carboxymethylcellulose (CMC), on the solubility ofbrimonidine tartrate at various pH conditions was determined. Thevarious concentrations of CMC tested with Brimonidine tartrate were 0%,0.056%, 0.17%, 0.5%, 1.5% (w/v), see Table III.

The samples tested also contained isotonic components, buffercomponents, and stabilized chlorine dioxide (Purite™), Table III. Sodiumcarboxymethyl-cellulose, sodium chloride, potassium chloride, calciumchloride dihydrate, and magnesium chloride hexahydrate were USP grade.Boric acid and sodium borate decahydrate were NF grade.

TABLE III Sample 1 Sample 2 Sample 3 Sample 4 Sample 5 Brimonidine  0.2% 0.2%  0.2%  0.2%  0.2% (w/v) tartrate CMC  0.0% 0.056%  0.17%  0.5% 1.5% (w/v) Stabilized chlorine 0.005%  0.005%  0.005%  0.005%  0.005% (w/v) dioxide^(a) Sodium chloride 0.58% 0.58% 0.58% 0.58% 0.58% (w/v)Potassium chloride 0.14% 0.14% 0.14% 0.14% 0.14% (w/v) Calcium chloride,0.02% 0.02% 0.02% 0.02% 0.02% (w/v) dihydrate magnesium chloride,0.006%  0.006%  0.006%  0.006%  0.006%  (w/v) hexahydrate boric acid 0.2%  0.2%  0.2%  0.2%  0.2% (w/v) sodium tetraborate, 0.14% 0.14%0.14% 0.14% 0.14% (w/v) decahydrate ^(a)Sold under the trademarkPurite ™ by Allergan, Inc.

Each sample (1 through 5) was brought to various points within a rangeof pH values from about 7 to about 10. The vials containing the samplesolutions were placed on a laboratory rotator and left to equilibratefor fifteen days at 21° C. The sample solutions were filtered using a 25mm diameter polysulfone cellulose acetate syringe type filter with 0.45μm pore size. The filtered solutions were assayed for the amount ofbrimonidine tartrate in solution.

Conventional HPLC and detection techniques were used to detect anddetermine the concentrations of soluble brimonidine tartrate. See TableIV. Solubility is plotted against pH for each CMC concentration. Theexperimental data points were fitted to a modified Henderson-Hasselbalchequation using a nonlinear least squares routine (Deltagraph version 4.0DeltaPoint, Inc.), See FIG. 1. The R² values show the statistical fitbetween the experimental values and the theoretical equation to begreater than 0.991.

TABLE IV Solubility of Brimonidine tartrate (% w/v) 1.5% pH 0% CMC0.056% CMC O.17% CMC 0.5% CMC CMC 6.67 0.9302 1.4464 6.68 1.4200 1.42566.93 0.7302 7.10 0.3693 7.11 0.2064 0.2828 7.35 0.1904 7.56 0.1451 7.680.0786 7.77 0.0721 7.81 0.0735 8.10 0.0498 8.46 0.0313 8.50 0.0286 8.550.0328 8.67 0.0311 9.93 0.0234 9.94 0.0250 10.05 0.0241 10.09 0.021810.11 0.0222

FIG. 1 clearly shows that the solubility of brimonidine tartrateincreases at a given pH as a function of CMC concentration. For example,at pH 7.5, the sample with 0% CMC resulted in 1000 ppm of Brimonidinetartrate; 0.056% CMC, 1300 ppm; 0.17% CMC, 1300 ppm; and 0.5%, 1600 ppm.At pH 7.5, the sample with 1.5% CMC resulted in about 1400 ppm, which isless than that of a similar solution with CMC at 0.5%. It is unclear atthis point what the cause of this observation may be. Nonetheless,brimonidine tartrate is more soluble in solution with a 1.5% CMC thanwith no CMC.

Nonetheless, brimonidine tartrate is clearly more soluble in solutionwith a 1.5% CMC than with no CMC.

CMC is also effective to solubilize Brimonidine tartrate in a biologicalenvironment, for example the biological environment of the cornea.

Example 3

Brimonidine tartrate is added to a test tube containing a compositionincluding chlorite. The test tube was allowed to equilibrate for tendays. Samples obtained from the test tube are analyzed by HPLC using asize exclusion column in the presence or absence of a chaotrope, such asurea. It is observed that a portion of the brimonidine tartrate monomerunits have conjugated to form dimmers, as measured by the apparentmolecular weights of brimonidine in solution.

Example 4

Brimonidine tartrate was formulated for ophthalmic topical delivery atpH 7.2 and a concentration of 0.15% (w/v) in an aqueous solutioncontaining PURITE® as a preservative. The ocular hypotensive efficacy ofthis formulation was determined in human clinical subjects, and comparedto the efficacy of ALPHAGAN®, which contains 0.2% brimonidine tartrate,formulated in aqueous ophthalmic topical solution at pH 6.5 in a citratebuffer with 0.05% benzalkonium chloride as a preservative. A thirdformulation containing 0.2% (w/v) brimonidine tartrate and a PURITE®preservative was also included as a control.

381 human subjects diagnosed with glaucoma or ocular hypertension wererandomly assigned to take one of the three formulations at a dosage ofone drop into each affected eye three times daily for 12 months.Intraocular pressure (IOP) is measured at two weeks, six weeks, 3months, 6 months, 9 months and 12 months.

At the end of the 12 month period, the results indicated that there wasno significant difference in the hypotensive efficacy of a solutioncontaining 25% less of the active ingredient (0.15% brimonidine) whenformulated at pH 7.2, as compared to the ALPHAGAN® product (0.2%brimonidine formulated at pH 6.5). However, those subjects receiving0.15% brimonidine reported a lower incidence of side effects, such asallergic conjunctivitis, oral dryness, conjunctival hyperemia, and eyedischarge, as compared to the higher (0.2%) concentration ofbrimonidine. These differences are not seen in the 0.2% brimonidinesolutions containing PURITE®, and thus are not attributable to thedifference in preservatives.

Example 5

A 0.1% brimonidine tartrate solution at pH 7.7 was made as follows:

TABLE V Brimonidine-Purite 0.1% Ophthalmic Solution Concentration (%Ingredient w/v) Concentration (mg/g) Brimonidine Tartrate 0.1 1.0Carboxymethylcellulose 0.5 5.0 Sodium Stabilized Oxychloro 0.005 0.05Complex (Purite ®) Boric Acid 0.6 6.0 Sodium Borate 0.045 0.45Decahydrate Sodium Chloride 0.37 3.7 Potassium Chloride 0.14 1.4 CalciumChloride 0.006 0.06 Dihydrate Magnesium Chloride 0.006 0.06 HexahydrateSodium Hydroxide adjust to pH 7.7 adjust to pH 7.7 Hydrochloric Acidadjust to pH 7.7 adjust to pH 7.7 Purified Water q.s. to 100% q.s. to100%

Example 6

A topical aqueous ophthalmic solution comprising 0.1% (w/v) brimonidinetartrate formulated at pH 7.7 (“BP 0.1%”) as indicated in Example 5, wasmade for testing in human clinical subjects suffering from high IOP, andthe efficacy of this solution compared to the efficacy of ALPHAGAN®,(0.2% brimonidine tartrate formulated in an citrate-buffered aqueousophthalmic topical solution at pH 6.5 with 0.05% benzalkonium chlorideas a preservative).

433 human clinical subjects were randomly chosen to receive one drop ofone of the two solutions in the affected eye three times daily.Intraocular pressure is measured at baseline (day 0), three weeks, sixweeks, and 3 months.

The results were as follows:

Baseline

The hour 0 IOP was identical for the two groups (24.7 mm Hg), and thehour 2 (˜23 mm Hg) and hour 8 (˜22 mm Hg) IOPs were similar for the twogroups.

Post-Baseline Hour 0 IOP

Mean TOP ranges for hour 0 post-baseline readings over the 3-monthfollow-up period were:

-   -   20.7 to 21.4 mm Hg (BP 0.1%)    -   21.0 to 21.7 mm Hg)(ALPHAGAN®)

Post-Baseline Diurnal IOP

Results at post-baseline time points were, in general, similar betweenthe treatment groups. At Month 3, ranges for the diurnal TOP group meansat hours 0, 2, and 8 were as follows:

-   -   17.2 to 21.4 mm Hg (BP 0.1%)    -   17.6 to 21.7 mm Hg)(ALPHAGAN®)        This study shows that, as between the BP 0.1% and the ALPHAGAN®        formulations, the subjects experienced substantially equivalent        efficacy over the period of the study. These results were        completely unexpected. However, probably because the BP 0.1%        only contained 50% the amount of the active ingredient,        brimonidine tartrate, as did the ALPHAGAN® formulation, the        number of reported incidents of side effects such as oral        dryness, asthenia, and eye pruritus were lower in the BP 0.1%        group as in the ALPHAGAN® group.

Example 7

Another variation of the formulation of 0.1% brimonidine tartrate at pH7.7 may be made according to the following table:

Concentration (% Ingredient w/v) Concentration (mg/ml) BrimonidineTartrate 0.1 1.0 Carboxymethylcellulose 0.5 5.0 Sodium Benzalkoniumchloride 0.005-0.01  0.05-0.1  (BAK) Sodium Phosphate 0.732 7.32(septahydrate) Sodium Citrate 0.1 1.0 (Dihydrate) (optional) SodiumChloride 0.66-0.69 6.6-6.9 Sodium Hydroxide adjust to pH 7.7 adjust topH 7.7 Hydrochloric Acid adjust to pH 7.7 adjust to pH 7.7 PurifiedWater q.s. to 100% q.s. to 100%

Example 8

Another variation of the formulation of 0.1% brimonidine tartrate at pH7.7 may be made according to the following table:

Concentration (% Ingredient w/v) Concentration (mg/ml) BrimonidineTartrate 0.1 1.0 Polyvinyl alcohol (PVA) 0.1-1    1-10.0 Preservative0.001-0.01   0.01-0.1   (e.g., cetrimide, chlorexidine, Polyquad, orPHMB) Sodium Phosphate 0.732 7.32 (septahydrate) Sodium Citrate 0-0.10-1   (Dihydrate) (optional) Sodium Chloride (optional)  0-0.69 0-6.9Sodium Hydroxide Adjust to pH 7.7 adjust to pH 7.7 Hydrochloric AcidAdjust to pH 7.7 adjust to pH 7.7 Purified Water q.s. to 100% q.s. to100%

It will be understood that sodium salts may be substituted by salts ofother metal cations, such as potassium or calcium. If present, tonicityagents may be salts or non-ionic tonicity enhancers, such as glycerin.Buffers may be made with any agent having the appropriate bufferingcapacity at the chosen pH. The concentrations given above are by way ofexample, and to not limit the invention in its broader aspects.

While this invention has been described with respect to various specificexamples and embodiments, it is to be understood that the invention isnot limited thereto and that it can be practiced with considerablevariation within the scope of the following claims by those skilled inthe art.

What is claimed is:
 1. A therapeutically effective aqueous ophthalmiccomposition comprising: a solution containing 0.1% (w/v) of a compoundselected from the group consisting of brimonidine, a salt ofbrimonidine, and an ester of brimonidine, wherein the solution furthercomprises an oxy-chloro preservative and carboxymethylcellulose, whereinthe composition has a pH between 7.0-8.0.
 2. The composition of claim 1which comprises about 0.1% (w/v) of brimonidine tartrate.
 3. Thecomposition of claim 1 which comprises 0.1% (w/v) of brimonidinetartrate.
 4. The composition of either of claim 3 wherein thecarboxymethyl cellulose enhances the solubility of brimonidine tartratein solution.
 5. The composition of claim 3 wherein the oxy-chlorocomponent is Purite.
 6. The composition of claim 3 further comprisingboric acid.
 7. The composition of claim 3 further comprising sodiumborate.
 8. The composition of claim 3 further comprising hydrochloricacid.
 9. The composition of claim 8 wherein the composition has a pH of7.4-8.0.